Soluble compounds released by hypoxic stroma confer invasive properties to pancreatic ductal adenocarcinoma

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Soluble compounds released by hypoxic stroma confer invasive properties to pancreatic ductal adenocarcinoma. / Liu, Dajia ; Steins, Anne ; Klaassen, Remy et al.

In: Biomedicines, Vol. 8, No. 11, 444, 01.11.2020, p. 1-23.

Research output: Contribution to journal › Article › Academic › peer-review

BibTeX

@article{54cb8198f86c4bbc8ff18f4ea1b9a5b4,

title = "Soluble compounds released by hypoxic stroma confer invasive properties to pancreatic ductal adenocarcinoma",

abstract = "Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and a hypoxic microenvironment. Pancreatic stellate cells (PSC) are activated by hypoxia and promote excessive desmoplasia, further contributing to the development of hypoxia. We aimed to explore how hypoxia and stroma interact to contribute to invasive growth in PDAC. [18F]HX4 PET/CT was found to be a feasible non-invasive method to assess tumor hypoxia in 42 patients and correlated with HIF1α immunohistochemistry in matched surgical specimens. [18F]HX4 uptake and HIF1α were strong prognostic markers for overall survival. Co-culture and medium transfer experiments demonstrated that hypoxic PSCs and their supernatant induce upregulation of mesenchymal markers in tumor cells, and that hypoxia-induced stromal factors drive invasive growth in hypoxic PDACs. Through stepwise selection, stromal MMP10 was identified as the most likely candidate responsible for this. In conclusion, hypoxia-activated PSCs promote the invasiveness of PDAC through paracrine signaling. The identification of PSC-derived MMP10 may provide a lead to develop novel stroma-targeting therapies.",

keywords = "Epithelial-to-mesenchymal transition, Hypoxia, Pancreatic ductal adenocarcinoma, Pancreatic stellate cells, Stroma",

author = "Dajia Liu and Anne Steins and Remy Klaassen and {van der Zalm}, {Amber P.} and Bennink, {Roel J.} and {van Tienhoven}, Geertjan and Besselink, {Marc G.} and Bijlsma, {Maarten F.} and {van Laarhoven}, {Hanneke W. M.}",

year = "2020",

month = nov,

day = "1",

doi = "10.3390/biomedicines8110444",

language = "English",

volume = "8",

pages = "1--23",

journal = "Biomedicines",

issn = "2227-9059",

publisher = "MDPI AG",

number = "11",

}

RIS

TY - JOUR

T1 - Soluble compounds released by hypoxic stroma confer invasive properties to pancreatic ductal adenocarcinoma

AU - Liu, Dajia

AU - Steins, Anne

AU - Klaassen, Remy

AU - van der Zalm, Amber P.

AU - Bennink, Roel J.

AU - van Tienhoven, Geertjan

AU - Besselink, Marc G.

AU - Bijlsma, Maarten F.

AU - van Laarhoven, Hanneke W. M.

PY - 2020/11/1

Y1 - 2020/11/1

N2 - Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and a hypoxic microenvironment. Pancreatic stellate cells (PSC) are activated by hypoxia and promote excessive desmoplasia, further contributing to the development of hypoxia. We aimed to explore how hypoxia and stroma interact to contribute to invasive growth in PDAC. [18F]HX4 PET/CT was found to be a feasible non-invasive method to assess tumor hypoxia in 42 patients and correlated with HIF1α immunohistochemistry in matched surgical specimens. [18F]HX4 uptake and HIF1α were strong prognostic markers for overall survival. Co-culture and medium transfer experiments demonstrated that hypoxic PSCs and their supernatant induce upregulation of mesenchymal markers in tumor cells, and that hypoxia-induced stromal factors drive invasive growth in hypoxic PDACs. Through stepwise selection, stromal MMP10 was identified as the most likely candidate responsible for this. In conclusion, hypoxia-activated PSCs promote the invasiveness of PDAC through paracrine signaling. The identification of PSC-derived MMP10 may provide a lead to develop novel stroma-targeting therapies.

AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and a hypoxic microenvironment. Pancreatic stellate cells (PSC) are activated by hypoxia and promote excessive desmoplasia, further contributing to the development of hypoxia. We aimed to explore how hypoxia and stroma interact to contribute to invasive growth in PDAC. [18F]HX4 PET/CT was found to be a feasible non-invasive method to assess tumor hypoxia in 42 patients and correlated with HIF1α immunohistochemistry in matched surgical specimens. [18F]HX4 uptake and HIF1α were strong prognostic markers for overall survival. Co-culture and medium transfer experiments demonstrated that hypoxic PSCs and their supernatant induce upregulation of mesenchymal markers in tumor cells, and that hypoxia-induced stromal factors drive invasive growth in hypoxic PDACs. Through stepwise selection, stromal MMP10 was identified as the most likely candidate responsible for this. In conclusion, hypoxia-activated PSCs promote the invasiveness of PDAC through paracrine signaling. The identification of PSC-derived MMP10 may provide a lead to develop novel stroma-targeting therapies.

KW - Epithelial-to-mesenchymal transition

KW - Hypoxia

KW - Pancreatic ductal adenocarcinoma

KW - Pancreatic stellate cells

KW - Stroma

UR - http://www.scopus.com/inward/record.url?scp=85094626538&partnerID=8YFLogxK

U2 - 10.3390/biomedicines8110444

DO - 10.3390/biomedicines8110444

M3 - Article

C2 - 33105540

VL - 8

SP - 1

EP - 23

JO - Biomedicines

JF - Biomedicines

SN - 2227-9059

IS - 11

M1 - 444

ER -

ID: 14087666

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